Maintenance of epithelial differentiation is one of the biological functions of vitamin A and explains current interest in this nutrient as a chemopreventative agent of epithelial cancer. Therefore, current research efforts center on the elucidation of possible sites and mechanisms of action of the vitamin. Retinoic acid can modify the composition of the carbohydrate moiety of the collagen-binding domain of fibronectin in cultured chicken sternal chondrocytes. This and other data are consistent with a role of the vitamin in glycoprotein biosynthesis, possibly as a result of its participation as a structural component of the membrane-associated retinyl phosphate mannose. This mannolipid, whose structure was confirmed by fast atom bombardment and collisional activation mass spectrometry, may be functioning in the membrane to generate guanosine diphosphate mannose. In support of this proposal are the in vivo results which demonstrate a decreased pool of guanosinediphosphate mannose and the lipid intermediate dolichyl phosphate mannose and the accumulation of shorter oligosaccharide chains on lipids and proteins in vitamin A-deficient hamster liver microsomal membranes. A similar condition of vitamin a deficiency was found in primary and transplanted minimally and maximally deviated hepatocellular carcinomas, suggesting the possibility that deficiency of vitamin A may be either a consequence of cell selection during carcinogenesis or a permissive condition for the development of the tumor from initiated cells. In cultured hamster tracheas vitamin A deficiency causes the predominance of the higher molecular weight species of keratin at the same time as squamous metaplasia and epithelial keratinization become visible. Current studies attempt to define whether changes in epithelial differentiation caused by deficiency of vitamin A may be the result of a direct action of the vitamin on gene expression or the effect of alterations in cell populations due to altered glycosylation reactions and incorrect positioning or function of adhesive molecules such as fibronectin at the cell surface.